Effects of leptin modulation on health span and lifespan

Project Summary/Abstract The overall objective of the research proposal is to explore the impact of leptin modulation on healthspan and lifespan. Aging is associated with a dramatic increase in visceral adiposity that contributes to elevated circulating leptin and leptin resistance. Our recent publications in Science Translational Medicine, Diabetes, Cell Metabolism and Molecular Metabolism have clearly indicated hyperleptinemia is a driving force for diet or antipsychotic drug-induced obesity and its associated metabolic disorders, and partial leptin reduction protects the mice from obesity and tissue dysfunction. Furthermore, our preliminary results suggest that chronic hyperleptinemia drives cellular senescence in cultured preadipocytes, proving a potential mechanism for increased inflammation and reduced capacity to differentiate into mature adipocytes. In addition, reducing circulating leptin, achieved by a genetic approach, significantly extend both median and maximum lifespan. Based on these observations, we proposed our central hypothesis that leptin modulation is a new means to regulate both healthspan and lifespan via leptin-driven cellular senescence. With our newly generated mouse models and customized leptin neutralizing antibody, along with numerous resources at San Antonio Nathan Shock Center, we will assess the effect of leptin modulation in healthspan and lifespan with three Specific Aims. Aim 1 is to test whether aging-associated hyperleptinemia accelerates cellular senescence and impairs healthspan and lifespan; Aim 2 is to access the effects of reducing leptin on cellular senescence, healthspan, and lifespan; Aim 3 will elucidate the underlying mechanism(s) mediating leptin-driven cellular senescence. All three Specific Aims work together to establish a novel mechanism for metabolic aging and set the stage for trials of leptin-based therapeutics in humans to reduce age-related diseases and extend healthspan and lifespan.